Diabetes remains a major and growing public health problem. Late stage complications of diabetes consume a large proportion of national health care resources.
Drugs acting as agonists toward PPAR-gamma (Peroxisome Proliferation Activator Receptor-gamma) are useful for treatment of Type 2 diabetes. They lower blood glucose and clear lipids contributing to insulin resistance from muscle, though at the expense of increased subcutaneous fat deposition and weight gain. Clinical use of PPAR-gamma agonists is also limited by fluid retention, increasing the risk of heart failure. In animals, doses of PPAR-gamma agonists within or only slightly outside the therapeutic range cause cardiac enlargement. There is a need for new therapies that effectively address the primary defects of insulin resistance and islet failure with fewer or milder side effects than existing drugs.
The use of certain compounds in combination with rosiglitazone or pioglitazone is disclosed in WO 02/100341, WO/073611, WO 04/091486, U.S. Provisional Patent Applications No. 60/667,457, filed Apr. 1, 2005, and No. 60/762,068, filed Jan. 25, 2006, all of which are assigned to Wellstat Therapeutics Corp.
Rosiglitazone, a direct PPAR-gamma agonist, is marketed in combination with other antidiabetes drugs as AVANDAMET® (rosiglitazone maleate and metformin hydrochloride) and as AVANDARYL® (rosiglitazone maleate and glimepride).